Promiscuous Phytochemicals: When Natural Products Seem to “Do it All”

From easing inflammation to ridding cells of toxins, phytochemicals like curcumin, resveratrol, sulforaphane, and berberine, seem to do it all.   Even after a skeptical appraisal of the scientific evidence, there is no discernable counterweight to the lineaments of a panacea.  

As a general class, phytochemicals are spectacles of polypharmacology, that is, having a tendency to ameliorate multiple underlying pathways in divergent models, ranging from brain neurons to bone cells.  

Still, it sounds too good to be true.  

To navigate the cutting edge of phytochemical-based therapies, it helps to appreciate several phenomena that complicate our ability to understand them.  

1. Promiscuity

Plants engineer their chemicals for the purpose of binding proteins—not ours, but those of their primordial enemies, like fungi, bacteria, yeast and insects.¹  A legacy of coevolution, these chemicals interact with diverse predatory proteins, and have thereby enabled plants to survive to this day.²

We’re not fungi or insects, but proteins aren’t as diverse as you might think.  There are only so many ways they can elongate and fold in three-dimensional space.   Even across taxonomic crevasses, popular architectural motifs simply never went out of style.  There’s enough redundancy to guarantee random encounters between our proteins and plants’ chemical deployments.¹

The scenery is further mottled by capricious functional groups that phytochemicals like to wear—groups that indiscriminately bind multiple targets.  Such catholic tastes always worked well for plants, who insisted on something far more theatrical than a simple stone’s throw.  Instead, they flung multifunctional chemicals like shrapnel across the kingdoms, thwarting bacteria, arresting yeast and even puckering the tastebuds of today’s herbivores.^1,2. 

2. Assay interference

The promiscuity and fickleness I just outlined are, collectively, a mismatch for conventional screening assays.

If you run six receptor binding assays, only to discover that the compound binds four, something’s wrong!  Quercetin and curcumin are examples of Pan-Assay Interference Compounds (PAINS), which tend to give false positive results in conventional screens by reacting nonspecifically with a litany of proteins, and even with each other (aggregation).³

Misguided insights can be avoided by adjusting methods based on structure-based assessment a priori (electrophiles, antioxidants, and Michael acceptors are often implicated) and by emphasizing more biologically representative assays that account for whole pathways.  Further, identifying active metabolites can also deconvolute the discovery landscape by shifting the focus toward smaller, simpler derivatives that often carry fewer violations.   All of these steps become far less important when there are compelling in vivo data.

Appropriately, with a growing interest in natural products, academic and industry researchers are adopting better methodologies to interrogate natural products from a wider, holistic lens of patterns and signatures, as opposed to singular proteins of yesteryear’s drug screens.  This is also the trend for nutrition research, which places a growing emphasis on phytochemicals as mediators of the health benefits of dietary plants (fruits, vegetables, herbs, spices and teas).

3. Multi-chemical sensing pathways 

We evolved with the capacity to sense plants in our diets.   Any plant, and whatever phytochemicals it wields.

An uptick in plant-eating alerted our bodies to prepare for two possible threats: (1) food shortage (running out of high-calorie meats, seeds, grain, etc), and (2) greater odds of ingesting a plant-borne toxin.  The legacy is a series of energy- and toxin- sensing pathways that not only proactively adjust our metabolic wiring, but strengthen our general resilience.  A gamut of phytochemicals can engage these multi-organ protective systems when consumed as isolated compounds.²

Notable examples are activation of the AMPK/SIRT1 axis, which improves mitochondrial function, insulin sensitivity and fat utilization, and the Nrf2-Keap1 pathway, which supports detoxification and antioxidant defenses. Anti-inflammatory effects of these pathways occur through cross-talk with NFkappaB, a genomic regulator of inflammatory cytokine expression that also responds to natural products in a generalized, yet favorable manner.  A third example is the microbiome, which is a major environmental sensor that regulates multiple organs indirectly.  

The pleiotropic resilience afforded by strategic manipulation of these systems has attracted substantial R & D interest in prospective modulators (many of which, by the way, were inspired by natural products).   Caloric restriction and exercise also modify these “golden hubs” of homeostasis, with far-reaching translational implications for complex diseases.

Implications for students and medical practitioners

1. Since complex diseases involve many pathways and many targets, multifunctional agents like phytochemicals hold considerable promise.
2. While phytochemicals modulate many attractive therapeutic targets in vitro, it’s always incorrect to assume that these events occur in vivo without accompanying animal or human clinical evidence.  
3. Compelling clinical data already support the efficacy of phytochemicals like sulforaphane, curcumin and resveratrol for a variety of conditions, and researchers are working backwards to figure out “how.”  While controversy persists regarding how they work, the clinical data are quite robust.  Focus on the clinical outcomes and you’ll make smart decisions.   
4. There’s no magic bullet.   But perched throughout Earth’s bountiful flora, there’s “magic shrapnel”.   We won’t find it unless we ask the right questions.  

References

1. Ho TT, Tran QTN, Chai CLL. The Polypharmacology of Natural Products.  Future Med Chem, 2018.
2. Heim KC, Spinella MJ.  Natural Products in the Prevention of Cancer: A Review.  In: Nutraceuticals and Functional Foods in Human Health and Disease Prevention.  D. Bagchi, HG Preuss, Anand Swaroop, Eds.   CRC Press, 2015.
3. Rydzewski RM.  Real World Drug Discovery:  A Chemist’s Guide to Biotech and Pharmaceutical Research. c. 2008 Elsevier Ltd.